AU2012231548A1 - Mixed crystal agomelatine (Form-VIII), preparation method and use thereof and pharmaceutical composition containing same - Google Patents
Mixed crystal agomelatine (Form-VIII), preparation method and use thereof and pharmaceutical composition containing same Download PDFInfo
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Abstract
The present invention provides a mixed crystal agomelatine (Form-VIII), the preparation method and use thereof and a pharmaceutical composition containing the same, wherein the mixed crystal mainly contains an agomelatine crystal form VI. The mixed crystal is stable and has good reproducibility, and is found through a stability test to be superior to a crystal form VI in terms of stability. Therefore, the Form-VIII of the present invention has an advantage in terms of preparation.
Description
"V "PCT/CN2012/072818 Mixed crystalline form VIII of agomelatine, its method of preparation method, application and pharmaceutical composition Technical field The present invention relates to a mixed crystalline form of agomelatine, N-[2 (7-methoxy-1-naphthyl)ethyl]acetamide, its method of preparation, application and pharmaceutical composition. Prior art Agomelatine, with chemical name N-[2-(7-methoxy- 1 -naphthyl)ethyl]acetamide and brand name Valdoxan, has the following chemical structure: 0 N
CH
3 MeO H (I) It has a dual effect, acting not only as an agonist of melatoninergic system receptors, but also as an antagonist of the 5HT 2 c receptor. Its properties mean that it is active in the central nervous system, especially in the treatment of severe depression, seasonal affective disorder, sleep disorders, cardiovascular diseases, digestive system diseases, insomnia and fatigue brought on by jet lag, eating disorders and obesity. Agomelatine is the first melatoninergic antidepressant, and is effective in the treatment of depression and the improvement of sleep parameters, while not affecting sexual function. The preparation and therapeutic use of agomelatine have been reported in the European patent EP0447285. In view of the pharmaceutical value of said compound, it is important to obtain a highly pure, stable crystalline form with good reproducibility in order for it to be advantageous in pharmaceutical preparation and stable enough for long-term storage without having specific requirements in terms of temperature, light, humidity or oxygen levels. The Chinese patents CN200510071611.6, CN200610108396.7, CN200610108394.8, CN200610108395.2, CN200910047329.2, CN200910245029.5 have made public the various crystalline forms as well as the preparation methods of agomelatine. Among these, in CN200910047329.2, the publicly disclosed crystalline form VI obtained through the process of acetic acid and water recrystallization has superior solubility over most of the existing publicly disclosed crystalline forms, thus possessing unique value with regard to its properties in pharmaceutical formulation. However, when placing crystalline form VI under extreme conditions (high temperature of 60*C) for 10 days, small amounts of crystal transition can occur.
VT% VU & U14 UUi I 1UkU[00 2 Researchers have focused on the search for a crystalline or mixed crystalline form possessing greater stability without compromising in terms of solubility. Advantageously, through exploring various preparation processes and comparisons of stability, the inventor has found a mixed crystalline form which, when placed under extreme conditions, offers superior stability over crystalline form VI. Said mixed crystal achieves greater stability without compromising the excellent solubility of crystalline form VI. It offers great reproducibility and under extreme conditions, stability in its preparation process, thus greatly increasing the feasibility of pharmaceutical formulation. Scope of the Invention The aim of the present invention is to provide a mixed crystalline form of agomelatine, form VIII, while also providing a preparation process. When compared with crystalline form VI, said form VIII offers greater stability under high temperature. In addition, it exhibits valuable pharmaceutical formulation properties. The mixed crystalline form VIII of agomelatine in the present invention may be used in the treatment of diseases of the melatoninergic system, sleep disorders, stress, anxiety, seasonal affective disorder, severe depression, cardiovascular diseases, digestive system diseases, insomnia and fatigue brought on by jet lag, schizophrenia, phobias, and depression. The present invention also aims to provide a method of preparation for form VIII of agomelatine which is simple in its operation and offers good reproducibility. A further aim of the present invention is to provide a pharmaceutical composition, which includes the mixed crystalline form VIII of agomelatine of this invention as well as pharmaceutically acceptable adjuvants or excipients. The said pharmaceutical composition can be configured to be used in different application routes, especially when administered either orally or via injection. According to the nature and severity of the illness, treatment may be administered via a regulated dosage based on the age and weight of the patient. The dosage may vary between 0.1mg and lg per day, being administered once only or several times. The following examples of X-ray diffraction diagrams of form VIII of agomelatine of the present invention use interplanar crystal spacing d, Bragg angle 20 and relative intensity (I%) to show: 200 d (A) Relative intensity (I%) 9.493 9.3085 12.86 9.809 9.0096 15.62 10.815 8.1735 13.10 11.171 7.9141 17.53 11.879 7.4439 64.67 12.770 6.9264 17.90 V. v mu niau.,o VLU1/UU1/U7251S 3 13.811 6.4065 17.10 14.939 5.9255 12.14 15.315 5.7808 10.48 16.085 5.5057 19.89 17.544 5.0510 48.47 18.491 4.7943 66.41 19.065 4.6512 24.02 19.538 4.5398 99.39 19.774 4.4861 100.00 20.801 4.2668 50.35 21.156 4.1961 30.66 21.807 4.0722 37.31 22.499 3.9486 22.63 23.032 3.8583 31.18 23.780 3.7387 39.67 24.610 3.6144 21.02 25.419 3.5011 30.30 27.075 3.2906 14.67 31.931 2.8004 14.14 When using X-ray diffraction to measure the crystallization of the present invention, sometimes owing to the measurement equipment or test conditions, the measured peaks show slight deviations in measurement; more specifically, for example there may be a deviation in measurement of the 20 value by approximately i0.2; even if extremely accurate equipment is used, a deviation of approximately ±0.1 may be seen. As a result, this deviation must be taken into consideration when determining each crystalline structure. XRD test conditions for said form VIII of agomelatine of the present invention: Instrument model: Bruker D8 ADVANCE X-ray diffractometer Experiment parameters: Detector: LynxEye detector Light source: CuKa 40 kV 40 mA Monochromator: Ni filter disc Divergence slit: 1 DivH.L.Slit: 1.0 mm Probe: LynxEye probe Scanning method: 0-0 continuous scanning Scanning range: 3*~45' Step length: 0.02* Scanning speed: 8.0*/min Scanning time: 5 min j aum~u.,ou JC'T/CN2012/072818 4 Scanning temperature: Room temperature Test conditions for DSC change-in-absorption diagram of said form VIII of agomelatine of the present invention: Instrument model: NETZSCH DSC 204F1 Experimental conditions: Crucible type: Standard aluminium crucible (perforated) Shielding gas: High purity nitrogen 20 ml/min Sweep gas: High purity nitrogen 60 ml/min Heating rate: 10*C/min Temperature range: Room temperature ~140 0 C The onset value of the endothermic peak of the DSC change-in-absorption diagram of the present invention is characterised by: onset value range being 97 98 0 C, the endothermic peak area being no lower than 90%, with the preferable ratio being 95-99%. When using DSC to measure the crystals of the present invention, sometimes owing to the measurement equipment or test conditions, the measured peaks show slight deviations in measurement;. more specifically, for example there may be a deviation in measurement of the onset value by approximately ±1*C, even if extremely accurate equipment is used, a deviation of approximately ±0.5*C may be seen. As a result, this deviation must be taken into consideration when determining each crystalline structure. TGA test conditions of the present invention: Instrument model NETZSCH TG 209F1 Experimental conditions: Crucible type: A1 2 0 3 Sweep gas: N 2 20 ml/min; shielding gas: N 2 10 ml/min Temperature range: Room temperature300*C Heating rate: 10*C/min The method of preparation of form VIII of the present invention involves dissolving agomelatine compound form II (Agomelatine-HCl-H 2 0) in acetic acid, to which sodium acetate is then added, water is then added dropwise to this reaction mixture and agitated at a temperature of 7-13'C in order to bring about crystallization, with the crystals then being separated from the solution. 0 H MeO Meo
.HCLH
2 0 (II) In the present invention as described, there are no special requirements in terms of the amount of acetic acid that is to be added as long as a sufficient amount is WU ZU12/1Zo3?o PCT/CN2012/072818 5 used to dissolve the raw materials, while heating can also be suitably applied to facilitate dissolution. The molar ratio of form II agomelatine compounds and sodium acetate is preferably of the order of 1:1-1.5, most optimally 1:1-1.1. In the preparation method of the present invention as described, the ratio of volume of acetic acid to water is 1:15-30. In a preferred embodiment of the preparation method for agomelatine form VIII in the present invention, when the temperature of the resulting reaction mixture reaches 12-18*C, and in particular when around 15*C, water is added dropwise in order to bring about crystallization. In a further preferred embodiment, when water is added dropwise to the resulting reaction mixture, agitation is then carried out at a temperature of around 10*C. This may be carried out over a period of around 1.5 hours in order to bring about crystallization. In another preferred embodiment, following the addition of sodium acetate, the reaction mixture is heated to 40-80'C, an appropriate, non-fixed, amount of activated carbon is then added, followed by agitation and filtration; said solution is then left to cool on its own, and water is added dropwise in order to bring about crystallization. The agomelatine form VIII provided by the present invention can be used in conjunction with pharmaceutically acceptable adjuvants or excipients for pharmaceutical formulation. The present invention results in a new form VIII of agomelatine, with greater stability compared to that of crystalline form VI, thus possessing advantages in production in terms of stability. According to the Chinese patent application CN 201010126254.X, form II agomelatine compounds as previously described may be produced by means of the following preparation method, where said preparation method involves reacting agomelatine with various forms of HCl in order to form a hydrate. The two methods are as follows: Agomelatine is firstly dissolved in a water-containing organic solvent, after which HCl gas is added, the solid crystals are washed and then dried; or else agomelatine is added to a solvent containing HCl, and the solid crystals are then washed and dried. If the first method is used, an overabundance of HCl may lead to a decrease in yield, while in the second method the amount of HCl present in the solvent is easily controlled. Therefore the second method is preferred. Specifically, agomelatine may be added to a water-containing organic solvent, followed by the dropwise addition of a solvent containing HCl. The solid crystals are then washed and then dried. Likewise, it is also possible to add agomelatine to an organic solvent, followed by the dropwise addition of an aqueous solution containing HCl. The solid crystals are then washed and then dried. The full contents of reference documents either quoted or mentioned in this application have been referenced.
WU 1UIi/izo205o PCT/CN2012/072818 6 Description of drawings Figure 1 shows the X-ray diffraction diagram of form VIII in embodiment 1 of the present invention; Figure 2 shows the DSC change-in-absorption diagram of form VIII in embodiment 1 of the present invention; Figure 3 shows the X-ray diffraction diagram of form VIII in embodiment 2 of the present invention; Figure 4 shows the DSC change-in-absorption diagram of form VIII in embodiment 2 of the present invention; Figure 5 shows the X-ray diffraction diagram of form VIII in embodiment 3 of the present invention; Figure 6 shows the DSC change-in-absorption diagram of form VIII in embodiment 3 of the present invention; Figure 7 shows the thermogravimetric analysis TGA curve of the product in embodiment 5 of the present invention. Details of the embodiments The following embodiments further describe the present invention but do not limit the scope thereof. Embodiment 1: 14g of agomelatine compound form II is dissolved in 55ml of acetic acid, to which 4.5g of sodium acetate is then added; the mixture is then heated to 60*C, after which 0.5g of activated carbon is added. Agitation is carried out for 2 hours after which the mixture is filtered; at a temperature of 15*C, 1L of water is then added dropwise. The solution gradually becomes turbid, and at a temperature of -10*C, agitation is carried out over 1.5 hours, followed by filtration, then washing and drying the filter cake at 45 0 C under vacuum until constant weight is achieved, resulting in 9.6g of white solid; (Refer to Figure 1 for X-ray diffraction diagram; refer to Figure 2 for DSC change-in-absorption diagram) Embodiment 2: 140g of agomelatine compound form II is dissolved in 490ml of acetic acid, to which 60g of sodium acetate is then added; the mixture is then heated to 60*C, after which 1.4g of activated carbon is added. Agitation is carried out for 1 hour after which the mixture is filtered; at a temperature of 15*C, 8.8L of water is then added dropwise. The solution gradually becomes turbid, and at a temperature of -10*C, agitation is carried out over 1.5 hours, followed by filtration, then washing and drying the filter cake at 45*C under vacuum until constant weight is achieved, resulting in 94g of white solid; 7 (Refer to Figure 3 for X-ray diffraction diagram; refer to Figure 4 for DSC change-in-absorption diagram) Embodiment 3: 66g of agomelatine compound form II is dissolved in 230ml of acetic acid, to which 21g of sodium acetate is then added; the mixture is then heated to 60*C, after which 1.3g of activated carbon is added. Agitation is carried out for 1 hour after which the mixture is filtered; at a temperature of 15*C, 6.9L of water is then added dropwise. The solution gradually becomes turbid, and at a temperature of -10'C, agitation is carried out over 1.5 hours, followed by filtration, then washing and drying the filter cake at 50*C under vacuum until constant weight is achieved, resulting in 49g of white solid; (Refer to Figure 5 for X-ray diffraction diagram; refer to Figure 6 for DSC change-in-absorption diagram) Embodiment 4: Agomelatine crystalline forms VI and VIII (obtained through embodiment 2) are each placed in thermostatic containers at a temperature of 40*C and stored for 20 days, with the stability of these samples being studied using the method of High Performance Liquid Chromatography. 1. Purity measurement of the sample Chromatographic conditions: Octadecyl silane chemically bonded silica is used as packing; a mixed solution of 10 mmol/L phosphate buffer (adjusted to pH 7.0 with sodium hydroxide) and acetonitrile in the ratio 2:7 by volume acts as the mobile phase; column temperature 40*C; and detection wavelength 220nm. Purity is measured using an internal standard method. In the mobile phase, crystalline forms VI and VIII are distributed into lmg/mL solutions, 1 OgL of each of which are then passed into a liquid chromatograph, with their chromatograms being recorded. 2. Assay of the Sample The reference sample purity measurement method was used, with measurements being made using an external standard method, the results can be seen in Table I. Table I Sample name Crystalline form VI Form-ViI Purity Content Purity Content Before storage 99.7% 100.1% 99.8% 100.3% After storage in the 99.6% 99.8% 99.7% 100.1% thermostatically controlled containers for 20 days WO 2012/126386 PCT/CN2012/072818 8 3. Measurement of water solubility The HPLC method was used to determine water solubility, with measurements being made using an external standard method. The results are shown in Table II. Table II Sample name Crystalline form VI Form-VIII Solubility (m ml 0.336 0.335 4. Determination of crystalline stability Measured using the pharmacopoeia stability assessment method: 1) Influencing factor testing (exposed for 10 days): High temperature (60*C), illumination (4500 lx), high humidity (92.5%RH, 25*C) 2) Accelerated testing (hermetically sealed for 6 months): Temperature 30*C, humidity 65%RH 3) Long term testing (hermetically sealed for 12 months): Temperature 25'C, humidity 60%RH Table III Sample name Crystalline form VI Form VIII Influencing High x* factor temperature Illumination High humidity Accelerated testing Long term testing (6 months) Long term testing (9 months) Long term testing (12 months) x *: - stable; x- unstable As can be seen from the test results, form VIII of agomelatine of the present invention clearly offers greater stability under high temperature and comparable solubility when compared with crystalline form VI. Its preparation method offers good reproducibility. In addition, it exhibits valuable pharmaceutical formulation properties.
wu zuizIizo5o PCT/CN2012/072818 9 5. Study into the preparation and stability of pharmaceutical compositions (crystalline form, purity and content) 1000 capsules prescribed (dosage: 25mg) Form VIII 25 mg Lactose 71.2 mg Magnesium stearate 1.3 mg Stearic acid 1.3 mg Starch (Starch 1500) 19.5 mg Sodium carboxymethyl starch (CMS- 6.5 mg Na) Subjected to the pharmacopoeia stability assessment method and undergoing influencing factor. testing (10 day exposure): High temperature (60*C), illumination (4500 lx), high humidity (92.5%RH, 25*C); Accelerated testing (hermetically sealed for 6 months): temperature 30*C, humidity 65%RH; Long term testing (hermetically sealed for 12 months): temperature 25*C, humidity 60%RH. The assessment results demonstrate that under the above conditions neither the crystalline form, purity nor content of the product underwent any changes. Consequently, the test results of the pharmaceutical ingredients and capsules of this product show that form VIII has a great potential in pharmaceutical production. Embodiment 5: Agomelatine compound crystalline form II lOg of agomelatine is added to a 100ml solution of ethyl acetate. At a temperature of 10*C, 4.6g of an aqueous solution of HCl (36%) is slowly added dropwise. Agitation is then carried out for 1 hour, followed by filtration and the resulting solid is washed twice in 10ml of ethyl acetate, then dried at a temperature of 40*C to obtain 10.2g of form II white solid; purity: 99.8%, yield: 88.7%. Cl elemental analysis: Theoretically calculated value: Cl content 11.91 wt % Measured value: Cl content 11.86 wt % Determination of crystal water content of agomelatine compound crystalline form II: The calculated theoretical crystal water content of C 15
HI
7 NO2-HCl-H 2 0 is 6.06 wt %. 5.1 The Fischer method (Chinese Pharmacopoeia 2010 edition, appendix VIII M) ' C1CN2012/072818 10 The product resulting from embodiment 5 was measured according to the Fischer method as mentioned above, and the crystal water content recorded was: 6.15 wt%. 5.2 Thermogravimetric analysis (Chinese Pharmacopoeia 2010 edition, appendix VIII Q) The product resulting from embodiment 5 was measured according to thermogravimetric analysis as mentioned above, and the loss of crystal water recorded was: 6.67 wt %, i.e. the crystal water content of the original product was 6.67 wt %. For TGA curve, please refer to Figure 7.
Claims (20)
1. Mixed crystalline form of agomelatine, its X-ray diffraction diagram having the following values for Bragg angle 20: 200
9.493 9.809
10.815
11.171 11.879
12.770
13.811
14.939
15.315
16.085
17.544
18.491
19.065 19.538 19.774
20.801
21.156 21.807
22.499
23.032 23.780
24.610
25.419
27.075
31.931 including crystals whose peak diffraction angles are within 20±0.2* of the above. 2. Mixed crystalline form of agomelatine, its X-ray diffraction diagram having the following values for interplanar crystal spacing d, Bragg angle 20 and relative intensity: 200 d (A) Relative intensity (I%) 9.493 9.3085 12.86 9.809 9.0096 15.62 10.815 8.1735 13.10 11.171 7.9141 17.53 VYIJ IuIM IAWU3O PC'T/CN2012/072818 12 11.879 7.4439 64.67 12.770 6.9264 17.90 13.811 6.4065 17.10 14.939 5.9255 12.14 15.315 5.7808 10.48 16.085 5.5057 19.89 17.544 5.0510 48.47 18.491 4.7943 66.41 19.065 4.6512 24.02 19.538 4.5398 99.39 19.774 4.4861 100.00 20.801 4.2668 50.35 21.156 4.1961 30.66 21.807 4.0722 37.31 22.499 3.9486 22.63 23.032 3.8583 31.18 23.780 3.7387 39.67 24.610 3.6144 21.02 25.419 3.5011 30.30 27.075 3.2906 14.67 31.931 2.8004 14.14 including crystals whose peak diffraction angles are within 20±0.2* of the above. 3. The mixed crystalline form of agomelatine according to claim 1 or 2, characterised by: its DSC change-in-absorption diagram, the onset value range being 97-98*C, the endothermic peak area being no lower than 90%, with the preferable ratio being 95-99%. 4. The preparation method for the mixed crystalline form of agomelatine according to any of claims 1-3, wherein form II agomelatine compounds are dissolved in acetic acid, to which sodium acetate is then added, followed by the dropwise addition of water to this reaction mixture, which is then agitated at a temperature of 7-13*C in order to bring about crystallization, with the crystals then being separated from the solution 0 C6 .HCI.H 2 0 vyJ IUIA/1U00 PCT/CN2012/072818 13 5. The preparation method according to claim 4, wherein the molar ratio of form II agomelatine compounds and sodium acetate is of the order of 1 : 1-1.5, most optimally 1 : 1-1.1. 6. The preparation method according to claim 4 or 5, wherein the ratio of volume of acetic acid to water is 1:15-30. 7. The preparation method according to any of claims 4-6, wherein when the temperature of the resulting reaction mixture reaches 12-18*C, and in particular when 15*C, water is added dropwise in order to bring about crystallization. 8. The preparation method according to any of claims 4-7, wherein water is added dropwise to the resulting reaction mixture which is then agitated at a temperature of 10*C in order to bring about crystallization. 9. The preparation method according to any of claims 4-8, wherein following the addition of the sodium acetate, the reaction mixture is heated to 40-80*C; the said solution is then left to cool on its own, and water is added dropwise in order to bring about crystallization. 10. A pharmaceutical composition, including the mixed crystalline form of agomelatine according to any of claims 1-3 and pharmaceutically acceptable adjuvants or excipients. 11. The pharmaceutical composition according to claim 10, used in the preparation of a medicament, with this medicament being used to treat diseases of the melatoninergic system. 12. The pharmaceutical composition according to claim 10, used in the preparation of a medicament, with this medicament being used to treat sleep disorders, stress, anxiety, seasonal affective disorder, severe depression, cardiovascular diseases, digestive system diseases, insomnia and fatigue brought on by jet lag, schizophrenia, phobias, or depression. 13. The pharmaceutical application of the mixed form of agomelatine according to any of claims 1-3, wherein the said pharmaceutical application relates to the treatment of diseases of the melatoninergic system. 14. The pharmaceutical application of the mixed crystalline form of agomelatine according to any of claims 1-3, wherein the said pharmaceutical application relates to the treatment of sleep disorders, stress, anxiety, seasonal affective disorder, severe depression, cardiovascular diseases, digestive system diseases, insomnia and fatigue brought on by jet lag, schizophrenia, phobias, or depression.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2011100706340A CN102690209A (en) | 2011-03-23 | 2011-03-23 | Mixed crystal of agomelatine (form-VIII), preparation method and application thereof and pharmaceutical composition containing the same |
CN201110070634.0 | 2011-03-23 | ||
PCT/CN2012/072818 WO2012126386A1 (en) | 2011-03-23 | 2012-03-22 | Mixed crystal agomelatine (form-viii), preparation method and use thereof and pharmaceutical composition containing same |
Publications (2)
Publication Number | Publication Date |
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AU2012231548A1 true AU2012231548A1 (en) | 2013-10-03 |
AU2012231548B2 AU2012231548B2 (en) | 2015-11-19 |
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AU2012231548A Ceased AU2012231548B2 (en) | 2011-03-23 | 2012-03-22 | Mixed crystal agomelatine (Form-VIII), preparation method and use thereof and pharmaceutical composition containing same |
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US (1) | US20140088197A1 (en) |
EP (1) | EP2690088B1 (en) |
JP (1) | JP6203171B2 (en) |
KR (1) | KR20130136546A (en) |
CN (2) | CN102690209A (en) |
AR (1) | AR085915A1 (en) |
AU (1) | AU2012231548B2 (en) |
BR (1) | BR112013024022A2 (en) |
CA (1) | CA2829690C (en) |
CY (1) | CY1118751T1 (en) |
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EA (1) | EA023278B1 (en) |
ES (1) | ES2626030T3 (en) |
GE (1) | GEP201606567B (en) |
HK (1) | HK1193086A1 (en) |
HR (1) | HRP20170575T1 (en) |
HU (1) | HUE034329T2 (en) |
LT (1) | LT2690088T (en) |
MA (1) | MA34959B1 (en) |
MD (1) | MD4484C1 (en) |
ME (1) | ME02731B (en) |
MX (1) | MX355551B (en) |
MY (1) | MY166444A (en) |
PL (1) | PL2690088T3 (en) |
PT (1) | PT2690088T (en) |
RS (1) | RS55918B1 (en) |
SG (1) | SG193305A1 (en) |
SI (1) | SI2690088T1 (en) |
WO (1) | WO2012126386A1 (en) |
ZA (1) | ZA201306761B (en) |
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PH12012000132A1 (en) * | 2011-06-09 | 2014-10-20 | Servier Lab | New co-crystals of agomelatine, a process for their preparation and pharmaceutical compositions containing them |
PL3027588T3 (en) * | 2013-07-29 | 2020-11-02 | Les Laboratoires Servier | Complexes of agomelatine and sulphonic acids, method for preparing same and pharmaceutical compositions containing them |
CN104529804A (en) * | 2014-12-11 | 2015-04-22 | 连云港金康医药科技有限公司 | New crystal form of agomelatine |
EP3075724B1 (en) | 2015-03-31 | 2023-07-12 | F.I.S.- Fabbrica Italiana Sintetici S.p.A. | Solid form of agomelatine |
EP3466923A1 (en) | 2017-10-09 | 2019-04-10 | KRKA, d.d., Novo mesto | Process for the preparation of agomelatine in crystalline form |
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FR2658818B1 (en) * | 1990-02-27 | 1993-12-31 | Adir Cie | NOVEL DERIVATIVES WITH NAPHTHALENIC STRUCTURE, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
FR2866335B1 (en) * | 2004-02-13 | 2006-05-26 | Servier Lab | NEW PROCESS FOR THE SYNTHESIS OF AGOMELATIN |
US7498466B2 (en) * | 2004-02-13 | 2009-03-03 | Les Laboratoires Servier | Process for the synthesis and crystalline form of agomelatine |
FR2889521B1 (en) * | 2005-08-03 | 2007-12-28 | Servier Lab | NOVEL CRYSTALLINE FORM III OF AGOMELATIN, PROCESS FOR PREPARING THE SAME AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
FR2889522B1 (en) * | 2005-08-03 | 2007-12-28 | Servier Lab | NOVEL IV CRYSTALLINE FORM OF AGOMELATIN, PROCESS FOR PREPARING THE SAME, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
FR2889523B1 (en) * | 2005-08-03 | 2007-12-28 | Servier Lab | NOVEL CRYSTALLINE FORM V OF AGOMELATIN, PROCESS FOR PREPARING THE SAME AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
FR2923482B1 (en) * | 2007-11-09 | 2010-01-29 | Servier Lab | NOVEL VI CRYSTALLINE FORM OF AGOMELATIN, PROCESS FOR PREPARING THE SAME AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
CN101585779B (en) * | 2009-03-10 | 2014-04-02 | 上海医药工业研究院 | New crystal form of Agomelatine, preparation method and use thereof |
WO2011006387A1 (en) * | 2009-07-11 | 2011-01-20 | 浙江华海药业股份有限公司 | Process for preparing agomelatine, crystals of agomelatine and preparing process thereof |
CN101723844A (en) * | 2009-11-21 | 2010-06-09 | 浙江华海药业股份有限公司 | Agomelatine crystal form B, preparation method thereof and medicinal composition containing same |
CN101955440B (en) * | 2009-07-17 | 2014-04-09 | 江苏万特制药有限公司 | Crystal form of agomelatine and preparation method thereof |
EP2319827A1 (en) * | 2009-11-09 | 2011-05-11 | Ratiopharm GmbH | Process for the production of polymorph form I of agomelatine |
CN101781226B (en) * | 2009-12-23 | 2012-03-28 | 天津泰普药品科技发展有限公司 | Agomelatine and medicine composition thereof |
CN101792400B (en) * | 2010-03-16 | 2013-01-30 | 华东师范大学 | Synthetic method for agomelatine |
WO2011154140A2 (en) * | 2010-06-10 | 2011-12-15 | Gador S.A. | New process for the preparation of n-[2-(7-methoxy-1-naphthyl)-ethyl]acetamide and new crystalline form |
WO2012046253A2 (en) * | 2010-10-08 | 2012-04-12 | Msn Laboratories Limited | Process for the preparation of n-[2- (7-methoxy-l-naphthyl) ethyl] acetamide and its novel crystalline forms |
CN102452952A (en) * | 2010-11-03 | 2012-05-16 | 天津药物研究院 | Preparation method of high-purity I-type agomelatine crystal |
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